TY - JOUR
T1 - Electrical Stimulation Enhances Cardiac Differentiation of Human Induced Pluripotent Stem Cells for Myocardial Infarction Therapy
AU - Ma, Ruilian
AU - Liang, Jialiang
AU - Huang, Wei
AU - Guo, Linlin
AU - Cai, Wenfeng
AU - Wang, Lei
AU - Paul, Christian
AU - Yang, Huang Tian
AU - Kim, Ha Won
AU - Wang, Yigang
N1 - Funding Information:
This work was supported by the National Institutes of Health grants HL-110740 and HL-107957 (Y.W.) and the National Natural Science Foundation of China (81520108004) (H.T.Y.). The authors thank Prof. Xiang Zhang in Genomics, Epigenomics, and Sequencing Core, University of Cincinnati, for RNA-seq assistance.
Publisher Copyright:
© 2018 Mary Ann Liebert, Inc.
PY - 2018/2/10
Y1 - 2018/2/10
N2 - Aims: Electrical stimulation (EleS) can promote cardiac differentiation, but the underlying mechanism is not well known. This study investigated the effect of EleS on cardiomyocyte (CM) differentiation of human induced pluripotent stem cells (hiPSCs) and evaluated the therapeutic effects for the treatment of myocardial infarction (MI). Results: Cardiac differentiation of hiPSCs was induced with EleS after embryoid body formation. Spontaneously beating hiPSCs were observed as early at 2 days when treated with EleS compared with control treatment. The cardiac differentiation efficiency of hiPSCs was significantly enhanced by EleS. In addition, the functional maturation of hiPSC-CMs under EleS was confirmed by calcium indicators, intracellular Ca2+ levels, and expression of structural genes. Mechanistically, EleS mediated cardiac differentiation of hiPSCs through activation of Ca2+/PKC/ERK pathways, as revealed by RNA sequencing, quantitative polymerase chain reaction, and Western blotting. After transplantation in immunodeficient MI mice, EleS-preconditioned hiPSC-derived cells significantly improved cardiac function and attenuated expansion of infarct size. The preconditioned hiPSC-derived CMs were functionally integrated with the host heart. Innovation: We show EleS as an efficacious time-saving approach for CM generation. The global RNA profiling shows that EleS can accelerate cardiac differentiation of hiPSCs through activation of multiple pathways. The cardiac-mimetic electrical signals will provide a novel approach to generate functional CMs and facilitate cardiac tissue engineering for successful heart regeneration. Conclusion: EleS can enhance efficiency of cardiac differentiation in hiPSCs and promote CM maturation. The EleS-preconditioned CMs emerge as a promising approach for clinical application in MI treatment. Antioxid. Redox Signal. 28, 371-384.
AB - Aims: Electrical stimulation (EleS) can promote cardiac differentiation, but the underlying mechanism is not well known. This study investigated the effect of EleS on cardiomyocyte (CM) differentiation of human induced pluripotent stem cells (hiPSCs) and evaluated the therapeutic effects for the treatment of myocardial infarction (MI). Results: Cardiac differentiation of hiPSCs was induced with EleS after embryoid body formation. Spontaneously beating hiPSCs were observed as early at 2 days when treated with EleS compared with control treatment. The cardiac differentiation efficiency of hiPSCs was significantly enhanced by EleS. In addition, the functional maturation of hiPSC-CMs under EleS was confirmed by calcium indicators, intracellular Ca2+ levels, and expression of structural genes. Mechanistically, EleS mediated cardiac differentiation of hiPSCs through activation of Ca2+/PKC/ERK pathways, as revealed by RNA sequencing, quantitative polymerase chain reaction, and Western blotting. After transplantation in immunodeficient MI mice, EleS-preconditioned hiPSC-derived cells significantly improved cardiac function and attenuated expansion of infarct size. The preconditioned hiPSC-derived CMs were functionally integrated with the host heart. Innovation: We show EleS as an efficacious time-saving approach for CM generation. The global RNA profiling shows that EleS can accelerate cardiac differentiation of hiPSCs through activation of multiple pathways. The cardiac-mimetic electrical signals will provide a novel approach to generate functional CMs and facilitate cardiac tissue engineering for successful heart regeneration. Conclusion: EleS can enhance efficiency of cardiac differentiation in hiPSCs and promote CM maturation. The EleS-preconditioned CMs emerge as a promising approach for clinical application in MI treatment. Antioxid. Redox Signal. 28, 371-384.
KW - calcium pathways
KW - cardiomyocytes
KW - cellular differentiation
KW - electric stimulation
KW - induced pluripotent stem cells
KW - myocardial infarction
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U2 - 10.1089/ars.2016.6766
DO - 10.1089/ars.2016.6766
M3 - Article
C2 - 27903111
AN - SCOPUS:85040825426
SN - 1523-0864
VL - 28
SP - 371
EP - 384
JO - Antioxidants and Redox Signaling
JF - Antioxidants and Redox Signaling
IS - 5
ER -